1. Field of the Invention
The present invention relates to a nucleic acid construct, metabolic disordered non-human animal and use thereof.
2. Description of the Related Art
Cholesterol is an important lipid in an organism, and also a component constituting various lipids. Cholesterol is absorbed via an intestinal tract by ingestion, or bio-synthesized from acetyl-CoA in liver. The bio-synthesized cholesterol is excreted from liver, reabsorbed in small intestine, and transported to liver via blood and re-used. In liver, a part of cholesterol is metabolized into bile acid. When the cholesterol level in vivo rises due to some disorders, hypercholesterolemia occurs, giving causes for onset of hyperlipemia and obesity. The onset mechanism of these diseases originated from hypercholesterolemia has not been elucidated sufficiently.
Reabsorption and conversion into bile acid of cholesterol (cholesterol metabolism) are mediated by respective specific transporters or enzymes. A liver X receptor (LXR) which is one of nuclear receptors is known to be involved in regulation of expression of genes encoding these proteins.
It is so far reported that the liver X receptor (hereinafter, referred to as LXR in some cases) includes two kinds of subtypes (liver X receptor α (hereinafter, referred to as LXRα in some cases), liver X receptor β (hereinafter, referred to as LXRβ in some cases))(see, e.g., Peet et al., Curr. Opin. Genet. Dev. 8; 571-575, 1988). LXRα is known to form a heterodimer with retinoid X receptor (RXR) which is one of nuclear receptors and bind to a transcription regulatory control region of a target gene, to regulate transcription of the target gene.
As a model animal for diabetes and obesity, several animals are provided. For example, ob/ob mouse (leptin knockout mouse) and db/db mouse (leptin receptor knockout mouse) are widely used as a genetically-obese model. These mice cause decrease in energy consumption in addition to increase in energy ingestion by hyperphagia, and express phenotypes such as hyperglycemia, hyperinsulinism, insulin resistance, increase in the weight of a white adipocyte, and the like. These mice are widely used for studies of diabetes and obesity including elucidation of physiological functions and pharmacological functions of leptin. “Obesity” is induced by chronic disproportion of energy ingestion (feeding) and energy consumption, namely, by disorder of energy metabolism, and causes significant increase in lethality as compared with an individual of normal body weight.
On the other hand, for example, Otsuka Long-Evans Tokushima Fatty (OLETF) rat (Kawano K. et al., Diabetes 1992; 41(11): 1422-1428) and ZDF rat (Zucker L. M. et al., Ann. N. Y. Accad. Sci. 1965; 131: 447-458) are widely used as a model for obesity and type II diabetes manifesting insulin resistance. These animals show recognition of decrease in the amount of pancreas β cells in any cases, thus, are used also for studies on fragility of pancreas β cells in onset of type II diabetes.
For covering in detail various symptoms of human obesity and pathologies of diabetes, manufacturing of further new types of diabetes and obesity model animals is required, and needed for investigation of causes and studies of treatment of obesity and diabetes, and the like. A study of application of model animals developed using an embryological engineering strategy is expected as a matter enabling elucidation of pathologies of obesity and diabetes as a multifactorial disease. Further, this is a study field admitted as inevitable since application thereof to development of new therapeutic methods and therapeutic drugs including gene therapy and regenerative medicine in addition to elucidation of onset and pathologies of obesity and diabetes is expected.